Cardiovascular disease is the leading cause of death in adults with diabetes mellitus, who have a four- to five-fold increase in mortality from vascular disease. The molecular mechanisms responsible for increased cardiovascular disease in diabetes and the hyperglycemia-induced signal transduction pathways that contribute to vascular cell responses associated with atherosclerosis are poorly understood. Our preliminary data and work by others suggest that hyperglycemia alters endothelial and vascular smooth muscle cell (VSMC) proliferation in ways that would promote atherosclerosis. Toward understanding how these changes are mediated, we have found that in VSMC hyperglycemia regulates that activity of a promoter element associated with growth stimulation, the serum response element (SRE). Moreover, our studies demonstrate that hyperglycemia activities a mitogen activity protein kinase (MAPK), ERK2. The MAPKs play a fundamental role in the transduction of signal from the plasma membrane to the nucleus. The hypothesis for the proposed studies is that activation of specific members of the MAPK family by hyperglycemia contributes to the effects of hyperglycemia on vascular cell proliferation and the development of atherosclerosis. The specific aims for the studies are to: (1) Examine the hypothesis that hyperglycemia activates specific members of the MAPK family (the ERKs, JNKs, and p38 kinase) in endothelial and VSMC. Given the disparate effects of the ERKs versus JUN and p38 kinases on cell proliferation and of hyperglycemia on endothelial and VSMC proliferation, a secondary hypothesis is that hyperglycemia will activate different subsets of MAPK's in endothelial and VSMC. (2) Identify nuclear targets of hyperglycemia-activated signal transduction pathways in endothelial and VSMC. (3) Examine the hypothesis that activation of members of the MAPK family mediates hyperglycemia-induced nuclear events described in specific aim 2. (4) Examined the hypothesis that activation of the MAPKs by hyperglycemia mediates hyperglycemia-induced alterations in endothelial and VSMC proliferation. Identifying the signaling pathways that mediate the effects of hyperglycemia on vascular cell function is critical to devising means to prevent these changes and their complications, such as atherosclerosis.